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Glycosylation of an N-Terminal Extension Prolongs the Half-Life and Increases the in Vivo Activity of Follicle Stimulating Hormone
Ist Teil von
The journal of clinical endocrinology and metabolism, 2003-07, Vol.88 (7), p.3227-3235
Ort / Verlag
Bethesda, MD: Endocrine Society
Erscheinungsjahr
2003
Quelle
Oxford Journals 2020 Medicine
Beschreibungen/Notizen
FSH is a key component in assisted reproductive technologies. Because of rapid clearance of the hormone, patients have to be treated with daily injections. To address this problem, a long-acting FSH mutein was created by introduction of additional N-linked glycosylation into the molecule. New glycosylation sites were introduced by two different approaches: structure-aided, site-directed introduction of sites within the FSH molecule and addition of N-terminal extensions. A mutein with the extension sequence ANITVNITV at the N terminus of the α-chain (FSH1208) was efficiently glycosylated at both new sites. This resulted in a molecule with increased size and charge, factors known to reduce renal clearance of proteins. FSH1208 was found to have a 3- to 4-fold increased serum half-life, compared with wild-type recombinant FSH. Furthermore, in spite of a lower in vitro activity, FSH1208 had a markedly increased in vivo potency, as shown by increased ability to augment the ovarian weight and stimulate the serum estradiol levels in rats. These characteristics make FSH1208 a possible candidate for improved infertility treatment.